The present invention relates generally to the field of microwave-assisted chemistry techniques, and in particular relates to more sophisticated techniques such as chemical synthesis carried out on relatively small volumes of reactants.
Microwave-assisted chemistry techniques are generally well established in the academic and commercial arenas. Microwaves have some significant advantages in heating certain substances. In particular, when microwaves interact with substances with which they can couple, most typically polar molecules or ionic species, the microwaves can immediately create a large amount of kinetic energy in such species which provides sufficient energy to initiate or accelerate various chemical reactions. Microwaves also have an advantage over conduction heating in that the surroundings do not need to be heated because the microwaves can react instantaneously with the desired species.
The term xe2x80x9cmicrowavesxe2x80x9d refers to that portion of the electromagnetic spectrum between about 300 and 300,000 megahertz (MHz) with wavelengths of between about one millimeter (1 mm) and one meter (1 m). These are, of course, arbitrary boundaries, but help quantify microwaves as falling below the frequencies of infrared radiation but above those referred to as radio frequencies. Similarly, given the well-established inverse relationship between frequency and wavelength, microwaves have longer wavelengths:than infrared radiation, but shorter than radio frequency wavelengths.
Because of their wavelength and energy, microwaves have been historically most useful in driving reactions in relatively large sample amounts. Stated differently, the wavelengths of most microwaves tend to create multi-mode situations in cavities in which the microwaves are being applied. In a number of types of chemical reactions, this offers little or no disadvantage, and microwave techniques are commercially well established for reactions such as digestion or loss-on-drying moisture content analysis.
Microwaves, however, have been less successfully applied to small samples of materials. Although some chemistry techniques have the obvious goal of scaling up a chemical reaction, in many laboratory and research techniques, it is often necessary or advantageous to carry out chemical reactions on small samples. For example, the availability of some compounds, may be limited to small samples. In other cases, the cost of reactants may discourage large sample sizes. Other techniques, such as combinatorial chemistry, use large numbers of small samples to rapidly gather a significant amount of information, and then tailor the results to provide the desired answers, such as preferred candidates for pharmaceutical compounds or their useful precursors.
Microwave devices with larger, multimode cavities that are suitable for other types of microwave-assisted techniques (e.g. drying, digestion, etc.) are generally less-suitable for smaller organic samples because the power density in the cavity is relatively low and non-uniform in its pattern.
Accordingly, the need for more focused approaches to microwave-assisted chemistry has led to improvements of devices for this purpose. For example, in the copending and commonly assigned (CEM Corporation, 3100 Smith Farm Road, Matthews, N.C. 28106) U.S. applications referred to above, and the commercially available devices sold under the assignee""s DISCOVER(trademark) trademark, the assignee of the present invention has provided a single mode focused microwave device that is suitable for small samples and for sophisticated reactions such as chemical synthesis. Single mode devices are also available from Personal Chemistry Inc., Boston, Mass., under the EMRYS(trademark) trademark.
The very success of such single mode devices has, however, created associated problems. In particular, the improvement in power density provided by single-mode devices can cause significant heating in small samples, including undesired over-heating in some circumstances.
Accordingly, some potential advantages remain to be accomplished. For example, in chemical synthesis the temperature at which a particular reaction is initiated, run or maintained can be critical to the reaction""s success. At various temperatures, products or reactants can degrade undesirably or competing reactions can form compounds other than those desired or intended. Because single mode instruments can be so efficient in heating certain materials, this efficiency can occasionally result in overheating of synthesis reactants and thus negate the advantage provided by the single mode instruments. Stated differently, the application of microwaves controls the efficiency of the reaction rather than the bulk temperature of the reactants (and potentially the solvent, if used). Thus, greater efficiency is gained when a greater amount of microwave energy can be applied without producing an undesired increase in the bulk temperature of the materials being irradiated. Thus, although bulk temperature is a factor to be controlled, it represents a by-product of the successful use of microwaves rather than a requirement.
Furthermore, most microwave temperature control is often accomplished using the duty cycle (the ratio of the duration (time) that a signal is on to the total period of the signal) of the microwave device; i.e., turning the applied power off and on again on a repeated basis. Thus, in many cases, when a microwave device is set to run at xe2x80x9c50% powerxe2x80x9d, the applied power (usually expressed in watts, W) remains the same, and the ratio of the duty cycle is reduced; i.e., the xe2x80x9conxe2x80x9d portion of the cycle is decreased and the xe2x80x9coffxe2x80x9d portion is increased. Although such macro control is suitable for larger samples or less sensitive chemical procedures such as digestion and moisture analysis, it can be quite unsatisfactory for carrying out sophisticated chemical reactions or for using the small samples that are typical for laboratory-scale organic synthesis techniques.
The duty cycle technique for moderating power, and thus secondarily temperature, also has the disadvantage of being somewhat inefficient. Stated differently, when the duty cycle is moderated, molecules are being intermittently, rather than continuously, excited by microwave radiation. Thus, instead of being maintained at a particular energy level or exposed to a continuous power level, the molecules are continually cycling between a microwave-excited and a normal or ground state. As a result, the advantages of using microwaves to apply energy to molecules for the purpose of initiating or accelerating sophisticated reactions can be compromised.
An extended discussion of the nature and situational disadvantages of the duty cycle in microwave assisted chemistry is set forth in commonly assigned U.S. Pat. No. 6,288,379, the contents of which are incorporated entirely herein by reference. In particular, a useful background discussion is set forth at column 1 line 66 through column 2 line 52.
Thus, although the duty cycle technique has it disadvantages and inefficiencies, it has historically been the only method available to prevent reactions of any type, and particularly sophisticated organic synthesis reactions, from proceeding above a desired temperature.
Accordingly, the needs exists for a microwave technique that can apply greater amounts of microwave energy without generating the high bulk temperatures that can be undesirable or even fatal to certain reactions and without sacrificing the advantages of the interaction of the microwaves with the reactants.
Therefore, it is ,an object of the invention to provide a microwave technique that can remain sensitive enough to control the temperature of sophisticated organic synthesis reactions, but without sacrificing the advantages of the interaction of the microwaves with the reactants as often as possible.
The invention meets this object with a method of carrying out microwave assisted chemical reactions in which the method comprises placing reactants in a microwave-transparent vessel, placing the vessel and its contents into a microwave cavity; and applying a continuous single mode of microwave radiation within the cavity and to the vessel and its contents while concurrently externally cooling the vessel.
In another aspect, the invention is a method of carrying out microwave assisted chemical reactions, comprising placing reactants in a microwave-transparent pressure resistant vessel and sealing the vessel, placing the sealed vessel and its contents into a microwave cavity, applying microwave radiation continuously within the cavity and to the vessel and its contents while monitoring the temperature of the vessel or its contents, and while concurrently externally cooling the sealed vessel and its contents.
In yet another aspect, the invention is a method of carrying out microwave assisted chemical reactions comprising placing reactants in a microwave-transparent vessel, placing the vessel and its contents into a microwave cavity, monitoring the temperature of the vessel or its contents, applying a continuous single mode of microwave radiation within the cavity and to the vessel and its contents until the temperature reaches a desired setpoint, and concurrently externally cooling the vessel and its contents while applying the continuous microwave radiation to maintain the temperature substantially at the setpoint.
In a further aspect, the invention is a method of carrying out chemical reactions at specific temperatures comprising applying energy to reactants in a vessel using a source other than conduction heating of the vessel or the reactants, while concurrently cooling the vessel by conduction by contacting the exterior of the vessel with a fluid.
In another aspect, the invention is a method of carrying out chemical reactions comprising applying energy to reactants in a vessel in an instrument that uses a source other than conduction heating of the vessel or the reactants to heat the reactants, concurrently cooling the vessel in the instrument by providing a flow of conduction fluid against the vessel in the instrument, concurrently monitoring the temperature of the vessel or its contents in the instrument, and adjusting the heating source to maintain the desired temperature at the cooling capacity that the instrument can provide to the, vessel.
In yet another aspect, the invention is an instrument for carrying out microwave assisted chemical reactions. In this aspect, the invention includes a microwave cavity, a microwave-transparent vessel in the cavity, a detector for monitoring the temperature of the vessel or its contents in the cavity, means for applying a continuous single mode of microwave radiation within the cavity and to the vessel and its contents until the temperature reaches a desired setpoint as measured by the detector, means for concurrently externally cooling the vessel and its contents while applying the continuous microwave radiation, and means for maintaining the temperature substantially at the setpoint while applying the microwave radiation.